The ability to rationally design ligands to biological receptors would revolutionalize biomedical research. The recent advances in structural biology provide access to atomic resolution structural models of biological receptors. The recent X-ray crystal structure determination of the first HIV protein, the HIV protease, is an example of such a triumph in the area of AIDS research. The proposed research seeks to utilize our understanding of structure and conformation to develop principles for the design of ligands, or other molecules with functional properties. A basic investigation of beta-sheet forming peptides will be undertaken that could lead to strategies to design inhibitors of the dimerization of the HIV aspartyl protease. LIgand design principles will be directed towards molecules that may, by virtue of their sheet forming properties, interfere with the binding interactions of CD4 with (1) the class II MHC protein HLA- DR or (2) the HIV envelope glycoprotein gp120. CD4 based target molecules will be synthesized and their binding properties will be evaluated. In the course of these studies, the solution structure of a recently synthesized 12.2 kDa polypeptide that serves as an HIV receptor will be pursued by 2D- NMR methods. This information will be used to improve on ligand design capabilities. Recent developments in peptide chemistry offer hope that rigid, ultra- stable helical molecules can be designed and synthesized for use as (inter alia) ligands to biological receptors. One approach makes use of the powerful 310-helix forming properties of the amino acid alpha- aminoisobutyric acid (Aib). We have used a crystal structure of an Aib- containing 310-helical peptide in order to design of a peptide mimic of the active site of the serine proteases. This compound will be synthesized and examined for hydrolase activity. Vinylogous polypeptides are a new class of materials that we have designed and recently synthesized. The conformational and ion conducting properties of molecules in this class will be determined, and one vinylogous peptides will be examined as a ligand to a class II molecule, HLA-DR1. Rationally designed transmembrane channel molecules will be prepared and their ion conducting properties will be determined. The specific targets of the proposed research are expected to function as (inter alia) photo-gated and rectifying channels.